Insomnia is a very common disorder, affecting from 20 to 40% of the adult population, with an increasing incidence in the elderly. Insomnia can be due to many causes. One of them is the disturbance of the normal regulating sleep-wake cycles. This asynchrony can result in pathological changes. A potential therapeutic treatment to alleviate this effect consists in re-synchronizing the sleep-wake cycles by modulating the melatonergic system (Li-Qiang Sun, Bioorganic & Medicinal Chemistry Letters 2005, 15, 1345-49).
Melatonin is a hormone secreted by the pineal gland in mammals being produced at night to aid the body in regulating sleep-wake cycles, and it is also responsible for the photoperiodic information, and for the modulation of the retina physiology. The secretion of melatonin in humans occurs simultaneously to nocturnal sleep, and the increase of melatonin levels is correlated with the increase of somnolence at nightfall. The amount of melatonin the body produces decreases with age, which may explain why the elderly suffer from insomnia more frequently than the general population. The therapeutic uses of melatonin in humans embrace the treatment of sleep delay syndrome and jetlag, including the treatment of nocturnal workers, and as hypnotic by itself. However, its short half-life (minutes) limits its therapeutic use. The synthesis of melatonin and the nocturnal secretion thereof are controlled by the supraquiasmatic nucleus, and are synchronized by the environmental light (Osamu Uchikawa et al., J. Med. Chem. 2002, 45, 4222-39; Pandi-Perumal et al., Nature Clinical Practice 2007, 3 (4), 221-228).
Melatonin receptors have been classified as MT1, MT2, and MT3, on the basis of pharmacological profiles. MT1 receptor is localized in the hypothalamic Central Nervous System, while MT2 receptor is distributed in the Central Nervous System and in the retina. The presence of MT1 and MT2 receptors has been disclosed also at peripheral level. MT1 and MT2 receptors are involved in a large number of conditions, such as depression, stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathology, pathology of the digestive system, insomnia or fatigue due to jetlag, schizophrenia, panic attack, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer's disease and cerebral circulation disorders. The MT3 receptor has been characterized as homologous to the quinone reductase-2 (QR2) enzyme. MT1 y MT2 receptors are coupled to G-Protein-coupled Receptor (GPCR) whose stimulation by an agonist produces a decrease in the adenylate cyclase activity and a subsequent decrease in the intracellular cAMP.
Synthetic melatonin receptors agonists have been object of intense research in recent years. In addition to its first use for insomnia, they may have potential application in the synchronization of disturbed circadian rhythms, sleep disturbances in the elderly, seasonal depression and jetlag, among many others. Furthermore, it has been shown that melatonin receptor agonists do not induce any of the hypothermic, hypotensive or bradycardic effects caused by melatonin in humans.
Ramelteon, N-[2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, has been the first melatonin receptors agonist approved by the US Food and Drug Administration (FDA) for therapeutic use in insomnia with no time limitation. Its mechanism of action is based on the agonism on MT1 and MT2 receptors. Ramelteon has no selectivity upon MT1 and MT2 receptors; however it shows selectivity on other central and peripheral receptors. Ki is 0.014 nM for MT1 and 0.045 nM for MT2. It shows a good absorption but suffers from an important metabolic first pass, being biotransformed in four metabolites.
Patent documents U.S. Pat. No. 4,600,723 and U.S. Pat. No. 4,665,086 disclose the use of melatonin to minimize the variations of the circadian rhythms induced by changes in the working schedules or the quick transit through diverse time zones (jetlag). Some compound series with melatonergic activity have been disclosed in patent documents EP848699B1, U.S. Pat. No. 5,276,051, U.S. Pat. No. 5,308,866, U.S. Pat. No. 5,633,276, U.S. Pat. No. 5,708,005, U.S. Pat. No. 6,143,789, U.S. Pat. No. 6,310,074, U.S. Pat. No. 6,583,319, U.S. Pat. No. 6,737,431, U.S. Pat. No. 6,908,931, U.S. Pat. No. 7,235,550, U.S. Pat. No. 7,297,711, WO8901472 and WO2005062992.
U.S. Pat. No. 6,034,239 discloses tricyclic melatonergic compounds of formula:

wherein A, B, m, R1, R2, R3, X, and Y have the meanings there indicated. Ramelteon belongs to this structure when A=(CH2)2, B has no additional substituents, R1=ethyl, R2═R3═H, m=2, X═CH2, Y═CH, dotted bonds are saturated bonds, and Y shows (S)— configuration (examples 19 and 20).
The approval of ramelteon represents an important milestone for the proof of concept of the melatonin target, and has opened new possibilities for research. However, there is an increasing need for new compounds with improved properties, such as higher potency and an increased resistance to metabolism, in order to provide more efficient treatments of conditions mediated by melatonin receptors.